The sirtuin SIRT6 regulates lifespan in male mice

Abstract

The significant increase in human lifespan during the past century confronts us with great medical challenges. To meet these challenges, the mechanisms that determine healthy ageing must be understood and controlled. Sirtuins are highly conserved deacetylases that have been shown to regulate lifespan in yeast, nematodes and fruitflies1. However, the role of sirtuins in regulating worm and fly lifespan has recently become controversial2. Moreover, the role of the seven mammalian sirtuins, SIRT1 to SIRT7 (homologues of the yeast sirtuin Sir2), in regulating lifespan is unclear3. Here we show that male, but not female, transgenic mice overexpressing Sirt6 (ref. 4) have a significantly longer lifespan than wild-type mice. Gene expression analysis revealed significant differences between male Sirt6-transgenic mice and male wild-type mice: transgenic males displayed lower serum levels of insulin-like growth factor 1 (IGF1), higher levels of IGF-binding protein 1 and altered phosphorylation levels of major components of IGF1 signalling, a key pathway in the regulation of lifespan5. This study shows the regulation of mammalian lifespan by a sirtuin family member and has important therapeutic implications for age-related diseases.

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Figure 1: Extended lifespan of male Sirt6 -transgenic mice.
Figure 2: Expression profile of differentially expressed genes in male Sirt6 -transgenic mice.
Figure 3: Alterations in the IGF1–AKT pathway in Sirt6 -transgenic males.

References

  1. 1

    Michan, S. & Sinclair, D. Sirtuins in mammals: insights into their biological function. Biochem. J. 404, 1–13 (2007)

    CAS  Article  Google Scholar 

  2. 2

    Burnett, C. et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477, 482–485 (2011)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Baur, J. A. et al. Dietary restriction: standing up for sirtuins. Science 329, 1012–1014 (2010)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Kanfi, Y. et al. SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell 9, 162–173 (2010)

    CAS  Article  Google Scholar 

  5. 5

    Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Viswanathan, M. & Guarente, L. Regulation of Caenorhabditis elegans lifespan by sir-2. 1 transgenes. Nature 477, E1–E2 (2011)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Rizki, G. et al. The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet. 7, e1002235 (2011)

    CAS  Article  Google Scholar 

  8. 8

    Herranz, D. et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nature Commun. 1, 3 (2010)

    ADS  Article  Google Scholar 

  9. 9

    Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006)

    CAS  Article  Google Scholar 

  10. 10

    Kawahara, T. L. et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-κB-dependent gene expression and organismal life span. Cell 136, 62–74 (2009)

    CAS  Article  Google Scholar 

  11. 11

    Kanfi, Y. et al. Regulation of SIRT6 protein levels by nutrient availability. FEBS Lett. 582, 2417–2423 (2008)

    CAS  Article  Google Scholar 

  12. 12

    Yuan, R. et al. Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 8, 277–287 (2009)

    CAS  Article  Google Scholar 

  13. 13

    Wang, C., Li, Q., Redden, D. T., Weindruch, R. & Allison, D. B. Statistical methods for testing effects on ‘maximum lifespan’. Mech. Ageing Dev. 125, 629–632 (2004)

    Article  Google Scholar 

  14. 14

    Yang, X. et al. Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res. 16, 995–1004 (2006)

    CAS  Article  Google Scholar 

  15. 15

    Tusher, V. G., Tibshirani, R. & Chu, G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl Acad. Sci. USA 98, 5116–5121 (2001)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Estep, P. W., III, Warner, J. B. & Bulyk, M. L. Short-term calorie restriction in male mice feminizes gene expression and alters key regulators of conserved aging regulatory pathways. PLoS ONE 4, e5242 (2009)

    ADS  Article  Google Scholar 

  17. 17

    Swindell, W. R. Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse. BMC Genomics 10, 585 (2009)

    Article  Google Scholar 

  18. 18

    Selman, C. et al. Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice. Physiol. Genomics 27, 187–200 (2006)

    CAS  Article  Google Scholar 

  19. 19

    Bauer, M. et al. Starvation response in mouse liver shows strong correlation with life-span-prolonging processes. Physiol. Genomics 17, 230–244 (2004)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Holzenberger, M. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Lee, P. D., Giudice, L. C., Conover, C. A. & Powell, D. R. Insulin-like growth factor binding protein-1: recent findings and new directions. Proc. Soc. Exp. Biol. Med. 216, 319–357 (1997)

    CAS  Article  Google Scholar 

  22. 22

    Yeap, B. B. et al. IGF1 and its binding proteins 3 and 1 are differentially associated with metabolic syndrome in older men. Eur. J. Endocrinol. 162, 249–257 (2010)

    CAS  Article  Google Scholar 

  23. 23

    Bluher, M., Kahn, B. B. & Kahn, C. R. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574 (2003)

    ADS  Article  Google Scholar 

  24. 24

    Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Conti, B. et al. Transgenic mice with a reduced core body temperature have an increased life span. Science 314, 825–828 (2006)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (2009)

    ADS  CAS  Article  Google Scholar 

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Acknowledgements

We thank R. S. Levy-Drummer, C. Wachtel, S. Schwarzbaum and members of the Cohen laboratory for their comments on the manuscript. This study was supported by National Institutes of Health grant 1RO1 GM085022 to Z.B.-J. and by grants from the Israeli Academy of Sciences, the United States - Israel Binational Science Foundation, the Israel Cancer Association, the Koret Foundation, the Israel Cancer Research Fund, the Israel Health Ministry, I-CORE program (41/1), the Israel Science Foundation and the European Research Council to H.Y.C.

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Contributions

H.Y.C. designed experiments, analysed data and contributed to writing the paper. Y.K. designed and performed experiments, analysed data and contributed to writing the paper. S.N. designed and performed experiments and contributed to writing the paper. G.A. performed the histopathological analysis. V.P. and L.N. performed experiments. G.Z. and Z.B.-J. developed analytical tools, analysed data and contributed to writing the paper. S.N and G.A. contributed equally to this work.

Corresponding author

Correspondence to Haim Y. Cohen.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-3 with legends, Supplementary Tables 1-4 and 7 (see Separate files for Supplementary Tables 5 and 6), Supplementary Methods and Materials with additional references and a Supplementary Comment. (PDF 6016 kb)

Supplementary Table 5

This table shows that all genes significantly changed between female WT vs. male WT (sheet 1), male Transgene vs. male WT (sheet 2), and female Transgene vs. female WT (sheet 3). (XLS 199 kb)

Supplementary Table 6

This table contains significantly over-represented Gene Ontology (GO) terms returned by FuncAssociate at an adjusted P-value cutoff of p<0.05. GO terms are listed in descending order of significance for differentially expressed (DE) genes between female WT vs. male WT (sheet 1) and male Transgene vs. male WT (sheet 2). GO analysis for the genes that are intersecting between DE genes in both fWT-mWT and mTG-mWT is listed in the last sheet. (XLS 190 kb)

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Kanfi, Y., Naiman, S., Amir, G. et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221 (2012). https://doi.org/10.1038/nature10815

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